Abstract/Project Summary Emerging evidence suggests mitochondrial dysfunction and impaired energy metabolism play a role in the development of Alzheimer's disease (AD). Our group previously reported reduced mitochondrial function in platelets isolated from blood of AD patients and in cytoplasmic hybrid cell lines generated with mitochondrial DNA from AD patients. Moreover, one of the early signs of AD is hypo-metabolism in the brain, further proof of mitochondrial dysfunction. Skeletal muscle mitochondria play a critical role in whole body aerobic capacity (VO2 peak), a powerful predictor of chronic disease and mortality risk. Mitochondrial dysfunction in skeletal muscle is also involved in whole body insulin resistance, which has emerged as a risk factor for AD. In support of these concepts, we have previously shown that AD patients have both reduced aerobic capacity and reduced insulin sensitivity compared to non-demented (ND) subjects of similar age and weight, strongly suggesting that AD patients also have skeletal muscle mitochondrial dysfunction. Potential causes for skeletal muscle mitochondrial dysfunction in AD patients is unclear but could be linked to an inactive lifestyle (chronic inactivity and sedentary lifestyle), which is increasingly linked to reduced cognition and AD risk and also accelerates skeletal muscle mitochondrial dysfunction that occurs with aging. In addition, genetics may play a role in the mitochondrial dysfunction found in AD. Apolipoprotein E4 (APOE ?4) carriers have the greatest risk for sporadic AD and animal models suggest that APOE ?4 impairs mitochondrial respiratory function via a pathological domain interaction. Therefore, it is possible that both lifestyle and genetic factors impact skeletal muscle mitochondrial function in AD patients but this has not been examined. To address this knowledge gap we will examine skeletal muscle mitochondrial-content, -enzyme activity, -respiratory capacity, and -H202 emission in skeletal muscle biopsies obtained from AD compared to age and sex matched ND subjects. To examine the role of genotype, we will recruit subjects that are APOE ?4 carriers or non-carriers in both the AD and ND groups (half of each group). To examine the role of lifestyle we will measure aerobic capacity (VO2 peak) and daily physical activity and sedentary behavior in all subjects. The first aim will test if skeletal muscle mitochondrial function and whole-body aerobic capacity are compromised in AD and in APOE ?4 carriers compared to ND and non-APOE ?4 carriers. The second aim will rank mitochondrial function and aerobic capacity function dependent upon AD status and genotype. This novel study examines how non-brain targets may drive AD susceptibility via lifestyle and/or genetic factors and could point to skeletal muscle mitochondria as a target for future therapies for prevention of AD.